Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.

Tumor-derived exosomes play critical roles in pancreatic ductal adenocarcinoma (PDAC) progression by mediating intercellular communication within the tumor microenvironment. This study identifies the long non-coding RNA PLBD1-AS1 as a functional oncogenic lncRNA enriched in PDAC exosomes. We demonstrate that PLBD1-AS1 promotes tumor cell proliferation, migration, and invasion by interacting with the glycolytic enzyme ALDOA and enhancing glycolytic flux. Furthermore, tumor exosomes deliver PLBD1-AS1 to pancreatic stellate cells (PSC), augmenting their glycolysis and facilitating their activation into cancer-associated fibroblasts, thereby shaping a pro-tumorigenic microenvironment. To target it, we developed an engineered exosome system modified with the tumor-penetrating peptide iRGD for specific delivery of siPLBD1-AS1 to both tumor and stromal cells. The resulting iRGD-exo-siPLBD1-AS1 construct demonstrated enhanced cellular uptake and effectively suppressed PLBD1-AS1 expression, inhibited glycolysis, impaired PSC activation, and significantly attenuated tumor growth. Our findings reveal a novel mechanism of exosome-mediated metabolic crosstalk in PDAC and establish a promising RNAi-based therapeutic strategy targeting this lethal malignancy.

Bladder cancer remains a significant therapeutic challenge due to its marked heterogeneity and capacity for immune evasion. Here, we employ spatial metabolomics and spatial transcriptomics to systematically characterize and visualize the metabolic and transcriptional landscapes of bladder cancer. Our findings identify distinct metabolic and transcriptional profiles across different tumor regions, highlighting heterogeneity and immune-associated metabolic reprogramming in BLCA. Further investigation identifies zinc finger protein 36 (ZFP36) as a potential immunotherapeutic target. Utilizing Zfp36 whole-body knockout and T cell-specific Zfp36 conditional knockout mice, we validated that Zfp36 knockout decreases the activation threshold for T cells and increases T cell infiltration in tumors. Moreover, we found that elevated ZFP36 expression is dramatically linked to worse patient outcomes. Mechanistically, ZFP36 facilitates mRNA degradation of key immune regulators, including C1QBP, thereby inhibiting T cell activation and cytotoxicity. Notably, combining Zfp36 knockout with anti-PD-1 therapy produced synergistic antitumor effects, suggesting that ZFP36 inhibition could be a promising therapeutic strategy. This integrated multiomics approach collectively uncovers immune-metabolic regulatory pathways in BLCA and points to critical molecular targets for immunotherapy.

Ewing sarcoma is driven by chromosomal translocations that fuse a FET RNA-binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to form de novo enhancers that activate oncogenic transcriptional programs essential for tumorigenesis. In addition to this truncal driver, recurrent loss-of-function alterations in the cohesin subunit STAG2 occur in approximately 10 to 15% of Ewing sarcomas and are associated with adverse clinical outcomes. However, how STAG2 loss reshapes EWS-FLI1 chromatin engagement and transcriptional output remains poorly understood. Here, using genetic STAG2 loss-of-function models combined with integrative multiomic profiling, we demonstrate that STAG2-cohesin deficiency reprograms the EWS-FLI1 chromatin landscape by altering its binding at GGAA-microsatellite enhancers. Despite increased EWS-FLI1 protein abundance, STAG2 loss eliminates over 40% of EWS-FLI1 binding sites, predominantly at enhancers containing short (1-4) GGAA repeats, while concurrently increasing binding at multimeric enhancers with ≥5 GGAA-repeat motifs. These reprogrammed sites show changes in both chromatin accessibility and H3K27ac, leading to selective amplification of EWS-FLI1 activity at multimeric microsatellite enhancers. By integrating Hi-C chromatin interaction maps with altered EWS-FLI1 occupancy, we define distinct monomeric and multimeric GGAA enhancer-driven transcriptional gene signatures and demonstrate that STAG2 loss selectively augments the multimeric transcriptional program. Consistently, the long GGAA microsatellite-activated gene signature is enriched in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that STAG2 loss reprograms, rather than globally attenuates, EWS-FLI1 function, amplifying a high-risk oncogenic transcriptional state in Ewing sarcoma.

Risk-reducing bilateral salpingo-oophorectomy is recommended to substantially lower ovarian cancer risk in women carrying BRCA1 or BRCA2 pathogenic variant (PV). The use of hormone replacement therapy (HRT) after risk-reducing bilateral oophorectomy (RRBO), although generally recommended, remains debated due to concerns about its possible role in breast cancer (BC) risk.

Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.

Members of the Lysine MethylTransferase 2 (KMT2) family are often abnormally expressed and mutated in many cancers. Similarly, several mutations listed in cancer databases map to key functional regions of KMT2 regulatory subunits, such as WD repeat domain 5 (WDR5), Retinoblastoma binding protein 5 (RbBP5), absent-small-homeotic-2-like (ASH2L), and DumPY-30 (DPY-30). In this study, we report the systematic characterization of cancer-associated mutations that map to regions important for the WDR5/RbBP5/ASH2L/DPY-30 (WRAD) complex formation. Both binding and thermal stability assays show that several cancer-related mutations do not affect ASH2L binding to DPY-30 or RbBP5. A subset of gain-of-function mutants highlights the role of long-range networks of interactions underlying RbBP5 binding by ASH2L. Parallel analysis of RbBP5 mutations shows additional variants that weaken its interactions with WDR5. Finally, systematic mapping of RbBP5 residues interacting with WDR5 defines the optimal WDR5-binding motif and shows that introducing hydrophobic residues beyond the central VDV sequence increases binding affinity. Overall, these findings reveal surprising gain-of-function mutations in ASH2L and provide a framework for targeting this epigenetic hub therapeutically.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, yet its genetic etiology remains poorly understood. In this study, we described a family from the Shanghai General Hospital Osteosarcoma (SGH-OS) cohort in which two siblings developed osteosarcoma as their first primary malignancy, and we investigated the germline and somatic genetic basis underlying this familial presentation.

Telomerase is active in the majority of high-risk neuroblastomas, a pediatric tumor associated with poor patient outcomes. In other cancer types, resistance to immune checkpoint blockade was overcome by induction of telomere dysfunction using the telomerase substrate precursor 6-thio-2'-deoxyguanosine (6-thio-dG). Here, we explored whether induction of telomere dysfunction improves the anti-tumor efficacy of immune checkpoint inhibition in neuroblastoma. 6-thio-dG treatment induced the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and programmed cell death ligand-1 (PD-L1) expression in murine neuroblastoma cells in vitro. In a MYCN;ALKF1174L-driven transgenic neuroblastoma mouse model, 6-thio-dG treatment delayed tumor growth and prolonged survival. Treatment with anti-PD-L1 also led to growth delay and improved survival, which occurred; however, only after an initial lag phase. Combination with anti-PD-L1 improved the anti-tumor effects of 6-thio-dG and overcame the initial lag phase of anti-PD-L1 treatment. Mechanistically, 6-thio-dG combined with anti-PD-L1 treatment induced cGAS and PD-L1 expression and promoted immune cell infiltration in the tumors. Our findings suggest that 6-thio-dG treatment activates the cGAS-STING pathway in neuroblastoma and that induction of telomere dysfunction in combination with immune checkpoint blockade boosts intratumoral immune cell infiltration and improves survival in a high-risk neuroblastoma mouse model.

Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

The bone marrow workshop (session 3), held at the 22nd Meeting of the European Association for Hematopathology/Society of Hematopathology in Dubrovnik, was dedicated to myeloid/lymphoid precursor cell neoplasms and mixed-phenotype acute leukemias (MPALs). We hereby report the clinicopathologic, immunophenotypic, and genetic features of the submitted cases.

The overall survival rate of acute myeloid leukemia (AML) remains less than 30%. Metabolic reprogramming of leukemia cells, such as the Warburg effect, enables them to adapt to the microenvironment and thereby develop. Elucidating the landscape of lactate regulation in AML helps clarify the pathogenesis from the perspective of metabolic reprogramming and identify possibilities for optimizing current treatment modalities.

Exosomes can promote tumor development and regulate tumor immune responses, making them of significant value in Lung Adenocarcinoma (LUAD) management. In-depth exploration of exosome-related genes in LUAD is of great significance for expanding LUAD clinical treatment options.

Bladder cancer is the tenth most common cancer worldwide and the sixth most common among men. However, research into representative tumor models for bladder cancer remains underdeveloped, limiting insights into tumor biology and drug development.

SpaFun is a novel, non-model-based method developed to address limitations in existing spatially variable gene detection techniques, particularly for large-scale spatially resolved transcriptomics datasets. These limitations include computational inefficiency, limited statistical power with increasing data size, and the inability to capture spatial heterogeneity and co-expression patterns among genes. Built on functional principal component analysis, SpaFun identifies domain-representative genes with significantly better computational efficiency and greater statistical power while accounting for spatial heterogeneity and co-expression patterns among genes. We applied SpaFun to three spatially resolved transcriptomics datasets and demonstrated that SpaFun outperformed state-of-the-art algorithms for identifying representative genes for tumor regions (e.g. DESeq, edgeR, and limma), as well as recently developed novel algorithms designed for spatial omics to identify the representative genes (e.g. SPARK and CSIDE). This highlights SpaFun's ability to accurately identify genes most representative of each spatial domain (e.g. tumor, immune, or stroma regions). By uncovering novel disease-relevant genes overlooked by existing algorithms, SpaFun could provide insights into new molecular mechanisms and propose innovative therapeutic strategies to improve patient outcomes.

Spatially resolved transcriptomic (ST) technologies offer transformative opportunities to chart gene expression landscapes within intact tissue architecture. Uncovering spatially discrete domains of biological function is essential for deciphering tissue heterogeneity, developmental processes, and disease mechanisms. Yet, the inherent noise, high dimensionality, and spatial sparsity of ST data present substantial challenges to the unsupervised delineation of these domains. We present SpatialDG, a dual-graph self-supervised contrastive learning framework for ST. SpatialDG combines graph neural networks with self-supervised contrastive learning to learn informative and discriminative spot representations by maximizing the agreement between local (node) and global (graph) embeddings and leveraging spatial adjacency to enhance representation learning. Specifically, SpatialDG constructs both a gene expression similarity graph and a spatial adjacency graph, integrating them via a dual-view contrastive architecture that aligns molecular and spatial information, while a zero-inflated negative binomial reconstruction loss accounts for the count-based and sparse nature of gene expression data. SpatialDG achieves significant gains over state-of-the-art algorithms in both healthy and cancer datasets, demonstrating robust generalization across diverse ST landscapes. In conclusion, SpatialDG efficiently unravels biologically meaningful domains from spatial and genetic signals, providing a powerful and generalizable tool to mine tissue architecture in ST datasets.

Angiogenesis, which is the formation of new blood vessels from existing vasculature, exhibits a pivotal role in breast cancer progression and promotes metastasis. This complex biological process is influenced by the dynamic balance of pro- and anti-angiogenic factors within the tumor microenvironment, such as vascular endothelial growth factor, fibroblast growth factors, and angiopoietins. Targeted therapeutic strategies have been developed to interfere with angiogenic signaling, aiming to normalize or inhibit the tumor vasculature. In recent years, miRNAs have arisen as crucial post-transcriptional regulators of gene expression implicated in angiogenic homeostasis. These microRNAs can function as either promoters or suppressors of angiogenesis by targeting mRNAs that encode angiogenic factors or other signaling molecules. Deregulated expressions of these miRNAs in BC are associated with perturbed angiogenesis, tumor progression, and therapeutic resistance. This review presents a thorough overview of the molecular processes controlling angiogenesis in BC and highlights the emerging roles of angioregulatory miRNAs. The article also discusses the therapeutic potential of targeting miRNAs to modulate tumor angiogenesis, providing novel insights for the development of miRNA-based diagnostics and therapeutics in BC management.

Germline sequencing is increasingly integrated into pediatric oncology, yet data on adolescents' experiences with genetic testing remain limited.

Pharmacovigilance has revealed an alarming correlation between certain medications and a higher risk of cancer. In this narrative review, included research from 2020 to 2025, along with a few seminal older studies, so that it provides a clear picture of which drugs actually set off cancer and mechanisms involved at the molecular level. An extensive literature review of the subject was designed on PubMed, Embase, Scopus, and Web of Science using systematic search. Search words and phrases included: "Carcinogenic drugs," "drug-induced cancer," "medication-induced carcinogenesis," "immunosuppressant cancer risk," "hormone therapy and cancer," "chemotherapy-induced secondary malignancies," and names of relevant drugs.

SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leverage genome-wide CRISPR-Cas9 screening in hundreds of cancer cell lines and identify the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation.